Intrathecal Zn²⁺ attenuates morphine antinociception and the development of acute tolerance

Vesicular Zn²⁺, released in the brain and from small dorsal root ganglion neurons, interacts with opioid as well as N-methyl-D-aspartate (NMDA) receptors. We investigated the effect of Zn²⁺ on morphine antinociception in mice (tail flick assay), as well as acute tolerance and dependence, phenomena associated with NMDA activity. Administered intrathecally (i.t.), Zn²⁺ inhibited morphine antinociception in a dose-related fashion. Zn²⁺ also inhibited acute tolerance to morphine antinociception (5 h after 100 mg/kg of morphine). Injection i.t. of di-sodium calcium ethylenediamine tetra acetic acid (Na⁺Ca²⁺ EDTA), a chelator of divalent cations, had no effect on analgesia, acute tolerance or acute dependence. However, withdrawal jumps produced by naloxone (1 mg/kg s.c.) in morphine-pellet implanted mice (3 days) were potentiated by injections twice daily of 10 nmol of Na⁺Ca²⁺ EDTA, suggesting that endogenous Zn²⁺ tends to inhibit long-term development of withdrawal. These data suggest that the availability of Zn²⁺ is an important factor in opioid activity. Copyright (C) 2000 Elsevier Science B.V.